Diffuse parenchymal pulmonary amyloidosis associated with multiple myeloma: A case report and systematic review of the literature

Pulmonary is an uncommon site of extramedullary involvement in multiple myeloma (MM). Diffuse parenchymal amyloidosis as pulmonary manifestation of MM is even rarer. We report a rare case of diffuse parenchymal pulmonary amyloidosis associated with MM diagnosed by video-assisted thoracoscopic lung biopsy (VATLB).

C A S E R E P O R T Open Access

Diffuse parenchymal pulmonary

amyloidosis associated with multiple

myeloma: a case report and systematic

review of the literature

Yin Liu1, Zhibin Jin2, Haiyan Zhang3, Yingwei Zhang1, Minke Shi4, Fanqing Meng5, Qi Sun5and Hourong Cai1*

Abstract

Background: Pulmonary is an uncommon site of extramedullary involvement in multiple myeloma (MM) Diffuse parenchymal amyloidosis as pulmonary manifestation of MM is even rarer We report a rare case of diffuse parenchymal pulmonary amyloidosis associated with MM diagnosed by video-assisted thoracoscopic lung biopsy (VATLB)

Case presentation: A 58-year-old woman complained of cough and shortness of breath HRCT disclosed diffuse ground-glass opacifications with interlobular septal thickening in bilateral lungs A lung-biopsy sample obtained

by VATLB revealed Congo Red-positive amorphous eosinophilic deposits in the alveolar septa Surgical biopsy of abdominal wall skin and subcutaneous fat was also performed, which showed the apple-green birefringence with polarized light on Congo red stain was demonstrated in dermis The serum immunoelectrophoresis showed monoclonal lambda light chains A bone marrow biopsy specimen comprised 11.5% plasma cells She was therefore diagnosed with diffuse parenchymal pulmonary amyloidosis accompanied by MM The patient was referred to the hematology department for further chemotherapy

Conclusions: It is important to recognize diffuse parenchymal pulmonary amyloidosis to avoid misdiagnosis Keywords: Diffuse parenchymal pulmonary amyloidosis, Multiple myeloma, Amyloidosis

Background

Amyloidosis is a rare disease characterized by the

depos-ition of insoluble misfolded proteins in various tissues

and organs Approximately 6–10 cases occur annually

per 100,000 in western Europe and the United States

[1–3] But the exact incidence is unknown

The respiratory system is involved in 50% of patients

with amyloidosis, although radiographic demonstration

is much less common [4,5] The respiratory amyloidosis

may be localized or part of systemic amyloidosis The

three main types of respiratory involvement are

tracheo-bronchial, nodular parenchymal, and diffuse parenchymal

pulmonary amyloidosis [4]

Diffuse parenchymal pulmonary amyloidosis, also known as diffuse alveolar-septal amyloidosis, is the least common type of pulmonary amyloidosis This type is sometimes seen in patients with multiple myeloma (MM) and is associated with a poor prognosis [6] In this article,

we will describe the clinical characteristics of a patient with diffuse parenchymal pulmonary amyloidosis associ-ated with MM diagnosed by video-assisted thoracoscopic lung biopsy (VATLB) in our hospital to improve our un-derstanding of this disease

Case presentation

A 58-year-old woman presented with a 2-year history of a non-productive cough and progressive shortness of breath She had a history of renal insufficiency and persistent proteinuria, without any extra-renal involvement She was diagnosed with IgA nephropathy for 15 years and had received immunosuppressive therapy for 6 years

* Correspondence: caihr@126.com ; caihourong2013@163.com

1 Department of Respiratory, Nanjing Drum Tower Hospital, Nanjing

University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu,

China

Full list of author information is available at the end of the article

© The Author(s) 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver

Her vital signs were stable at initial examination; the

patient was afebrile and oxygen saturation was 95% in

ambient air On physical examination, auscultation of the

lungs detected slight coarse crackles at the bilateral bases

The remainder of the examination was unremarkable

Her hemoglobin was 95 g/L but renal function and

calcium level were normal The patient was negative for

antinuclear and antineutrophil cytoplasmic antibodies in

immunofluorescence assays Repeated exams of sputum

smear did not yield any pathogenic micro-organisms

Serum free light chain analysis showed measuring

lambda light chain of 2.59 g/L Serum protein

electro-phoresis revealed low IgG, IgA, and IgM levels, with

reported immunoelectrophoresis (IEP) showing

mono-clonal lambda light chain peak with the monomono-clonal

protein A 24-h urine contained 5521 mg of protein

High-resolution chest CT revealed disclosed ground-glass

opacities (GGOs) with interlobular septal thickening in

bi-lateral lungs (Fig 1a and b) Chest and abdominal CT

shows soft tissue infiltration of the subcutaneous fat layer

with asymmetric bulging of the chest and abdominal wall

(Fig.1candd) Pulmonary function tests revealed a

mod-erately restrictive ventilation disorder, with a forced vital

capacity (FVC) of 1.76 L (69.0% of predicted) and severe

reduction of diffusion capacity (DLCO SB 20.8% of

pre-dicted) Cardiac biomarkers, such as natriuretic peptides,

particularly B-type natriuretic peptide (BNP) and cardiac

troponin-T were normal Echocardiogram showed normal

left ventricular ejection fraction of 61% and there were no

features of cardiac amyloidosis A VATLB was performed,

which showed marked thickening of the alveolar wall deposition of amorphous eosinophilic amyloid at the bronchial mucosa, pulmonary vessel wall and interstitium Congo red staining display apple-green birefringence in polarised light (Fig 2a andb) The immunohistochemical stain for protein A was negative for secondary amyloid Following the VATLB results, bone marrow examination was performed Bone marrow examination showed 11.5% plasma cells with lambda light chain restriction Bone marrow cells by flow cytometry exhibited a typical pheno-type for plasma cells, expressing monoclonal cytoplasmatic CD138, CD38, and cLambda instead of CD19, CD56 and cKappa, which are characteristic of the typical immunophe-notype of MM Fluorescence in situ hybridization (FISH) was carried out to check on the bone marrow aspirate The most frequent abnormality in the patients was 1q21 ampli-fication (25%), followed by 14q32 (IGH) translocations (29.5%), without 13q14 (RB1) deletion, 13q14.3 (D13S319) deletion and p53 deletion No lytic bone lesions were detected with positron emission tomography/computed tomography (PET/CT) This confirmed the diagnosis of

MM, λ light chain type, stage I Surgical biopsy of ab-dominal wall skin and subcutaneous fat was also per-formed, which showed the apple-green birefringence with polarized light on Congo red stain was demon-strated in dermis (Fig.3aandb

She was therefore diagnosed with diffuse parenchymal pulmonary amyloidosis accompanied by MM The pa-tient was referred to the hematology department, where the patient started chemotherapy with bortezomib and

Fig 1 Chest and abdominal CT (a, b) showed ground-glass opacities with interlobular septal thickening in bilateral lungs (c, d) showed soft tissue infiltration of the subcutaneous fat layer with asymmetric bulging of the chest and abdominal wall

dexamethasone, and her symptoms relieved 2 months

after the initial presentation No adverse effects were

ob-served and the laboratory results were stable

Discussion and conclusion

MM accounts for 1% of all cancers and 10% of all

hematologic malignancies [7] Amyloidosis is a rare

compli-cation associated with MM The most commonly affected

organs are the kidneys, heart, spleen, lymph nodes and the

liver [8] Pulmonary is an uncommon site of extramedullary

involvement in MM Diffuse parenchymal amyloidosis as

pulmonary manifestation of MM is even rarer; only a few

cases have been reported [8–14]

Diffuse parenchymal amyloidosis is characterized by the

presence of amyloid deposits in the alveolar septa and

ves-sel walls Pathologic examination of diffuse parenchymal

pulmonary amyloidosis shows deposition of amorphous

eosinophilic amyloid in the alveolar septa, especially around

the capillary vessels [15] Therefore, HRCT findings in such

patients mainly comprise GGOs, interlobular septal

thick-ening, intralobular reticular opacity, and nodules [1, 16]

Diffuse amyloidosis is sometimes accompanied by

medias-tinal lymphadenopathy Pleural effusion may be present

and occasionally dominate the clinical course Multiple cysts and calcification probably resulting from fragile alveolar walls as a consequence of amyloid deposition both on alveolar walls and around capillaries have been de-scribed [17] Differential considerations of diffuse parenchy-mal pulmonary amyloidosis are quite broad and include pneumonia, pneumoconiosis, interstitial lung disease and lymphangitic carcinomatosis

Diffuse parenchymal pulmonary amyloidosis has a re-markably different, more clinical presentation Such pa-tients may develop symptoms of coughing and shortness

of breath secondary to the amyloid deposits It is charac-terized by widespread amyloid deposition involving small vessels and the interstitium [18] This is reflected by lung function tests showing a restrictive pattern with re-duced diffusion capacity of carbon monoxide and hypox-aemia upon exertion [8] Affected individuals are more likely to progress to pulmonary hypertension and re-spiratory failure [1]

Tissue biopsy is the gold standard for the diagnosis and typing of amyloidosis Diagnosis of amyloidosis is confirmed by the presence of apple-green birefringence under polarized light of a tissue biopsy stained with

Fig 2 Histopathology of lung biopsy a Congo red staining showed marked thickening of the alveolar wall deposition of amorphous eosinophilic amyloid at the bronchial mucosa, pulmonary vessel wall and interstitium b Congo red staining display apple-green birefringence in polarised light

Fig 3 Histopathology of abdominal wall skin and subcutaneous fat a Hematoxylin and eosin (H&E) staining of the biopsy specimen revealed deposits of acellular amyloid matrix in dermis b The apple-green birefringence with polarized light on Congo red stain was demonstrated

in dermis

Congo Red [5] The diagnosis of pulmonary amyloidosis

is extremely important and requires histological analysis

to differentiate it from other interstitial lung diseases

The diagnosis of pulmonary amyloid can be made by

fiberoptic bronchoscopy, VATLB, and open thoracotomy

Although transbronchial lung biopsy (TBLB) is useful in

some amyloidosis cases, it may be of less efficacy in

establishing diagnosis due to the limit of the amount

biopsy sampling The lung VATLB is highly specific and

sensitive The biopsy of a clinically suspected organ is an

invasive procedure and may be associated with

compli-cations including hemorrhage Because amyloidosis is a

systemic disease, routine biopsies from nonsymptomatic

sites including the rectal mucosa, abdominal fat pad and

labial salivary glands are more commonly used [19] But,

clinical and radiological manifestations of subcutaneous

amyloidosis are very rare In our case, diffuse soft tissue

infiltration of the subcutaneous fat layer with asymmetric

bulging of the chest and abdominal wall were

demon-strated on CT Surgical skin biopsy including the

subcuta-neous fat pad can be performed safely and is useful for

diagnosing amyloidosis [20,21]

Once the diagnosis is clear, diffuse parenchymal

pulmon-ary amyloidosis requires intervention The therapeutic goal

for patients with concurrent pulmonary amyloidosis and

MM is suppression of the production of amyloid protein

comprising immunoglobulin light chain [7, 22]

Monoclo-nal antibodies such as daratumumab (Dara, human IgG1

anti-CD38) have shown promising efficacy for the

treat-ment of relapsed and refractory MM and heavily pretreated

amyloidosis [23,24] Therapy was well tolerated

Prospect-ive studies of daratumumab alone or in combination with

chemotherapy are warranted Treatment of systemic

amyl-oidosis aims at reducing the clonal cell populations

produ-cing amyloidogenic immunoglobulins, using high-dose

chemotherapy followed by autologous stem cell

transplant-ation in carefully selected patients Its efficiency in treating

diffuse pulmonary amyloidosis has not been established

Lung transplantation for isolated pulmonary amyloidosis

has been reported [25] The AL amyloid then contributed

to pulmonary hypertension (PH) with severe symptoms

necessitating lung transplantation Ellender et al described

a case with PH from amyloidosis secondary to systemic

lupus erythematosus and Sjögren’s syndrome, the patient

received bilateral lung transplantation and remained stable

after 7 years post lung transplantation [26] Lung

trans-plantation for isolated pulmonary amyloidosis or combined

with PH may be performed in highly selected patients with

good long-term outcome

Diffuse parenchymal amyloidosis is usually a systemic

phenomenon with a poor prognosis A median survival

for untreated patients is 13 months, and with the

devel-opment of heart failure the survival duration decrease to

less than 4 months [18] When compared with nodular

pulmonary amyloidosis, patients with diffuse parenchymal pulmonary amyloidosis has a far worse prognosis [10] Gradual worsening of pulmonary function and symptoms

is typical

In conclusion, diffuse parenchymal pulmonary amyloid-osis is a fatal disorder that is rare and often undiagnosed Radiologists and physicians should consider amyloid in clinically perplexing chronically ill patients, particularly those with plasma cell dyscrasias or chronic inflammatory states Tissue biopsy is the gold standard With the use of subcutaneous fat pad and lung biopsy, an early diagnosis can be made

Abbreviations

BNP: B-type natriuretic peptide; FISH: Fluorescence in situ hybridization; FVC: Forced vital capacity; GGOs: Ground-glass opacities; IEP: Immunoelectrophoresis; MM: Multiple myeloma; PET/CT: Positron emission tomography/computed tomography; PH: Pulmonary hypertension; TBLB: Transbronchial lung biopsy; VATLB: Video-assisted thoracoscopic lung biopsy

Acknowledgements

I wish to thank all the authors for advice and help on the case report.

Availability of data and materials The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Authors ’ contributions

YL wrote the manuscript and all authors carefully revised the manuscript YL performed a literature review and data collection to present, write, and revise the proposed manuscript ZBJ and HYZ cared for and followed up the patient YWZ, MKS, FQM and QS assisted with the presentation of findings and assisted with drafting and revising the manuscript HRC managed this case and gave his expert recommendations All authors have read and approved the final version of this manuscript.

Ethics approval and consent to participate Not applicable.

Consent for publication Written informed consent was obtained from the patient for publication of the case report.

Competing interests The authors declare that they have no competing interests.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author details

1 Department of Respiratory, Nanjing Drum Tower Hospital, Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China.2Department of Ultrasound, Nanjing Drum Tower Hospital, Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China 3 Department of Respiratory, Huainan Chaoyang Hospital, 15 Renmin South Road, Huainan 232000, Anhui, China 4 Department of Thoracic Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China 5 Department of Pathology, Nanjing Drum Tower Hospital, Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China.

Received: 10 January 2018 Accepted: 30 May 2018

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